4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative and process for producing 4-(1-carboxyalkyl)azetidin-2-one derivative using the same

ABSTRACT

A 4-(1,1-dialkoxycarbonylalkyl )azetidin-2-one derivative represented by formula (I): ##STR1## wherein R 1  and R 2  are identical or different and each represents an alkyl group, an alkenyl group, or an aralkyl group, R 3  represents a lower alkyl group, R 4  represents a hydrogen atom or a hydroxyl-protective group, and R 5  represents a hydrogen atom or an amino-protective group, and a process for producing a 4-(1-carboxyalkyl)azetidin-2-one derivative represented by formula (II) useful as an intermediate for 1β-alkylcarbapenem-type antibacterials: ##STR2## wherein R 3  represents a lower alkyl group and R 4  represents a hydrogen atom or a hydroxyl-protective group, which comprises de-esterifying and decarboxylating the derivative represented by formula (I), and in the case where an amino-protective group is present in the derivative of formula (I), eliminating the protective group from the derivative, are disclosed.

FIELD OF THE INVENTION

The present invention relates to a novel 4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative and a process forproducing, from the derivative, a 4-(1-carboxyalkyl)azetidin-2-onederivative which is useful as an intermediate for various1β-alkylcarbapenem-type antibacterial agents.

BACKGROUND OF THE INVENTION

Carbapenem-type antibacterial agents are excellent antibacterials havingstrong antibacterial activity against a wide spectrum of bacteriaranging from gram-positive bacteria to gram-negative bacteria includingPseudomonas aeruginosa. Hence, new antibacterials of the carbapenem-typeare being energetically developed in recent years. Although carbapenemderivatives having no substituent at the 1-position in the carbapenembackbone, such as thienamycin shown by formula (III): ##STR3## havedrawbacks that they are chemically unstable at high concentrations andthat they are readily metabolized by dehydropeptidase I, incorporationof a β-configuration alkyl group at the 1-position improves thestability of such carbapenem derivatives and enables the derivatives tobe used alone without the necessity of addition of a dehydropeptidaseinhibitor thereto. Therefore, efforts are currently being made todevelop 1β-alkylcarbapenem-type antibacterials and also to developmethods of synthesizing 4-[(R)-1-carboxyalkyl]azetidin-2-one derivativesrepresented by formula (IIβ): ##STR4## (wherein R³ represents a loweralkyl group and R⁴ represents a hydrogen atom or a hydroxyl-protectivegroup), which derivatives can be used as intermediates for suchantibacterials.

As synthetic methods for compounds (IIβ) described above, many reportshave been made. The most promising method of these is to alkylate a4-acetoxyazetidin-2-one derivative represented by formula (IV): ##STR5##(wherein R⁴ has the meaning as defined above and Ac denotes an acetylgroup) at the 4-position with any of various nucleophilic agents therebyto incorporate a side chain. With respect to this method, the followingreports, for example, have been made: alkylation with a propionic acidester enolate [C. U. Kim et al., Tetrahedron Lett., 28 (5) 507-510(1987); T. Chiba et al., Chem. Lett., 1343-1346 (1985); and T. Shibataet al., Tetrahedron Lett., 26 (39) 4739-4742 (1985)]; alkylation with apropionimide enolate [Y. Nagao et al., J. Am. Chem. Soc., 108, 4673-4675(1986); Yoshimitsu Nagao, Kayak (Chemistry), 42 (3) 190-196 (1987); L.M. Fuentes et al., J. Am. Chem. Soc., 108, 4675-4676 (1986); R. Dezielet al., Tetrahedron Lett., 27 (47) 5687-5690 (1986); and Y. Ito et al.,Tetrahedron Lett ., 28 (52) 6625-6628 (1987)]; and alkylation with apropionic acid thiol ester enolate [M. Endo, Can. J. Chem., 65,2140-2145 (1987); C. U. Kim et al., Tetrahedron Lett., 28 (5) 507-510(1987); and A. Hartei et al., Can. J. Chem., 66, 1537-1539 (1988)].

Other methods for synthesizing compounds (IIβ) include, for example, amethod of alkylating compound (V) ##STR6## (wherein R⁴ has the meaningas defined above) with lithium diisopropylamide [D. H. Shih et al.,Heterocycles, 21 (1) 29-40 (1984)] and a method in which theexo-methylene group of compound (VI) ##STR7## (wherein R⁴ has themeaning as defined above, R⁵ represents a hydrogen atom or anamino-protective group, and R⁶ represents. an alkyl group, a carboxylgroup, or an alkoxycarbonyl group) is reduced by catalytic reduction orby asymmetric reduction using a specific catalyst [JP-A-58-26887(corresponding to European Patent 71908B); C. U. Kim et al., TetrahedronLett., 28 (5) 507-510 (1987); T. Ohta et al., J. Org. Chem., 3176-3178(1987); and T. Iimori et al., Tetrahedron Lett., 27 (19) 2149-2152(1986)]. (The term "JP-A" as used herein means an "unexamined publishedJapanese patent application".) These methods are reported in Yoshio Itohet al., Yuki Gosei Kagaku (Chemistry of Organic Syntheses), 47 (7)606-618, "Synthesis of the 1β-Methylcarbapenem Key Intermediates"(1989).

According to these methods, compound (IIβ) in most: cases is obtained inthe form of compound (II) ##STR8## (wherein R³ and R⁴ each has themeaning as defined above) which is a mixture, in a specific proportion,of the compound (IIβ) and compound (IIα) ##STR9## (wherein R³ and R⁴each has the meaning as defined above) which is a stereoisomer with thecompound (IIβ). This compound (IIα) having an α-configuration alkylgroup can be converted to the desired compound (IIβ) having aβ-configuration alkyl group by isomerization, which may be conducted bythe method disclosed, for example, in D. H. Shih et al., Heterocycles,21 (1) 29-40 (1984).

However, the above-described methods for synthesizing compounds (II) and(IIβ) are disadvantageous in that special and expensive reagents areused, reaction temperature extremely low, or expensive or toxic metalsare used as catalyst. Therefore, the above methods are unsuited forsyntheses in large quantities and are not being practiced on anindustrial scale.

Hence, there has been a desire for development of process forefficiently producing compound (II), especially compound (IIβ) which hasa β-configuration alkyl group and is more useful as an intermediate for1β-alkylcarbapenem-type antibacterials.

SUMMARY OF THE INVENTION

Under these circumstances, the present inventors have conductedintensive studies. As a result, it has been found that a4-(1-carboxyalkyl)azetidin-2-one derivative can be produced efficientlywhen it is synthesized by a method in which a4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative having astructure in which a malonic acid derivative has been bonded to theazetidin-2-one backbone at the 4-position is first synthesized and thisazetidin-2-one derivative is then de-esterified and decarboxylated and,in the case where an amino-protective group is present in thederivative, the protective group is eliminated. The present inventionhas been completed based on this finding.

Accordingly, the present invention provides a4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative represented byformula (I): ##STR10## wherein R¹ and R² are identical or different andeach represents an alkyl group, an alkenyl group, or an aralkyl group,R³ represents a lower alkyl group, R⁴ represents a hydrogen atom or ahydroxyl-protective group, and R⁵ represents a hydrogen atom or anamino-protective group.

The present invention further provides a process for producing a4-(1-carboxyalkyl)azetidin-2-one derivative represented by formula (II):##STR11## wherein R³ and R⁴ each has the meaning as defined above, whichcomprises de-esterifying and decarboxylating the derivative of formula(I), and in the case where an amino-protective group is present in thederivative of formula (I), eliminating the protective group from thederivative.

DETAILED DESCRIPTION OF THE INVENTION

The 4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative of thepresent invention is represented by formula (I) described above.

Examples of the alkyl group of R¹ and R² in the formula includestraight-chain or branched alkyl groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, and tert-butyl; and monocyclic or polycyclic alkylgroups such as cyclopentyl, cyclohexyl, menthyl, fenchyl, and bornyl.Examples of the alkenyl group of R¹ and R² include straight-chain orbranched alkenyl groups such as vinyl, allyl, 2-butenyl, and2-methyl-2-propenyl. Examples of the aralkyl group of R¹ and R² includebenzyl and benzhydryl. Preferably, R¹ and R² are identical and eachrepresents a 2-alkenyl group.

The lower alkyl group of R³ is an alkyl group having 1 to 4 carbonatoms. Examples of the lower alkyl group include methyl, ethyl, andn-propyl. Of these, a methyl group is particularly preferred.

Examples of the hydroxyl-protective group of R⁴ include tri-substitutedsilyl groups such as trimethylsilyil and tert-butyldimethylsilyl; acylgroups such as acetyl; and aralkyl groups such as benzyl.

Examples of the amino-protective group of R⁵ include tri-substitutedsilyl groups such as trimethyisilyl, triethylsilyl,tert-butyldimethylsilyl, and methyldiphenyl-silyl; aralkyl groups whichmay have a substituent on the aromatic ring(s), such as benzyl,p-methoxybenzyl, p-tert-butylbenzyl, 3,4-dimethylbenzyl, phenethyl, andbenzhydryl; and alkoxyalkyl groups such as tetrahydropyranyl andmethoxymethyl. Of these groups, tri-substituted silyl groups arepreferred.

In the case where such 4-(1,1-dialkoxycarbonyl-alkyl)azetidin-2-onederivatives are represented by formula (I) in which R⁵ is a hydrogenatom (hereinafter referred to as "azetidin-2-one derivatives (Ia)"),these compounds can be produced according to, for example, the methodproposed by R. Joyeau et al., J. Chem. Soc., Perkin Trans. I, 1899-1907(1987); Tetrahedron Lett., 30 (3) 337-340 (1989) in which a malonic acidderivative (VII) is reacted with a 4-acetoxyazetidin-2-one derivative(IV) as shown by the following scheme: ##STR12## (wherein R¹, R², R³,R⁴, and Ac each has the meaning as defined above).

Illustratively stated, a 4-acetoxyazetidin-2-one derivative (IV) isadded to a solution of a malonic acid derivative (VII) which has beenactivated, for example, with an alkali metal such as potassium metal,sodium metal, or lithium metal, an alkali metal hydride such as sodiumhydride, an alkyl alkali metal such as butyllithium, an alkali metalalkoxide such as potassium tert-butoxide, sodium ethoxide, or sodiummethoxide, an alkali metal hydroxide such as potassium hydroxide orsodium hydroxide, an alkali metal carbonate such as potassium carbonate,or the like. The reactants in the resulting mixture are then allowed toreact at a temperature of from -60° to 40° C., especially preferably atroom temperature (20°-30 ° C.), for a period of preferably from 0.5 to15 hours, more preferably from 2 to 5 hours thereby to produce thedesired compound. Examples of the solvent for use in the above methodinclude water; alcohols such as methanol and ethanol ethers such asdiethyl ether, dioxane, and tetrahydrofuran; acetone; dimethylformamide;and mixed solvents consisting off water and one or more of such organicsolvents. Of these, tetrahydrofuran is especially preferably used. Theproportions of the reactant compounds are preferably such that themalonic acid derivative (VII) is used in an amount of about from 1 to1.3 mol, particularly about 1.1 mol, per mol of the4-acetoxyazetidin-2-one derivative (IV). The azetidin-2-one derivative(Ia) thus obtained can be purified by extraction washing, dehydration,and so forth, which may be conducted in an ordinary way, followed byrecrystallization, column chromatography, etc.

In the case where the 4-(1,1-dialkoxycarbonyl-alkyl)azetidin-2-onederivative of the present invention is represented by formula (I) inwhich R⁵ is an amino-protective group (hereinafter referred to as"azetidin-2-one derivative (Ib)"), this compound can be produced byobtaining an azetidin2-one derivative (Ia) in which R⁵ is a hydrogenatom, according to the method described above, and then incorporating anamino-protective group into the derivative (Ia) by an ordinary method.For instance, a tri-substituted silyl group can be incorporated into thederivative (Ia) as the amino-protective group by reacting the derivative(Ia) with a tri-substituted silyl chloride in a solvent such asN,N-dimethylformamide, acetonitrile, or tetrahydrofuran in the presenceof a base such as triethylamine, diisopropylamine, or pyridine at -20°to 30 ° C. for the night to a week, according to the method described inJP-A-58-26887 (corresponding to European Patent 71908B), and an aralkylgroup or an alkoxyalkyl group can be incorporated by reacting thederivative (Ia) with R--X (wherein R represents an aralkyl group or analkoxyalkyl group and X represents a halogen atom) in the above solventin the presence of an alkali such as potassium hydroxide, sodiumhydroxide, or sodium hydride at 0° to 30 ° C. for 3 to 24 hours,according to the method proposed by D. Reuschling et al., TetrahedronLett., (7) 615-618 (1978).

Further, according to the present invention, compound (I) thus obtainedis de-esterified and decarboxylated by an ordinary method, whereby a4-(1-carboxyalkyl)azetidin-2-one derivative (II) can be obtained.##STR13## (wherein R¹, R², R³, R⁴, and R⁵ each has the meaning asdefined above.)

The de-esterification and decarboxylation reactions can, for example, beperformed by hydrolysis and heating in an ordinary way. Illustrativelystated, compound (I) is hydrolyzed in the presence of a base, such assodium hydroxide, potassium hydroxide, or lithium hydroxide, and thehydrolyzate is then decarboxylated by heating it to 80° to 120° C. Inthe case where R¹ and R² are an aralkyl group, the de-esterification mayalso be accomplished by hydrogenation which is conducted using palladiumcarbon in the presence of an amine.

In the case where compound to be used as a raw material is representedby formula (I) in which R¹ and R² are a 2-alkenyl group, it is possibleto carry out the de-esterification and decarboxylation reactions by themethod described above. However, it is preferable that thede-esterification and decarboxylation reactions of such compound (I) beperformed by reacting formic acid or an amine salt of formic acid withthe compound (I) in the presence of a palladium compound; this is anapplication of, for example, the method proposed by J. Tsuji et al.,Tetrahedron Lett., (7) 613-616 (1979). This method is preferred in thatboth de-esterification and decarboxylation can be carried out in asingle step. As the palladium compound for use in the above method, anypalladium compound may be employed as long as it is capable ofgenerating zerovalent palladium, which is an active species, in thereaction system. Examples of such palladium compounds include divalentpalladium compounds such as palladium acetate, palladium chloride, andpalladium acetylacetonate; and zero valent palladium compounds such astribenzylidenedipalladium and tetrakis(triphenylphosphine)palladium.Along with the palladium compound described above, a trialkylphosphinesuch as triethylphosphine or tributylphosphine, a triarylphosphine suchas triphenylphosphine or tritolylphosphine, or the like is used as acompound to be a ligand. Due to the presence of both the palladiumcompound and the ligand compound, a complex is formed in the reactionsystem and functions as a catalyst to accelerate the reaction. Thisreaction may be conducted using a solvent, e.g., an ether such as1,4-dioxane or tetrahydrofuran, toluene, or benzene, by heating thereaction mixture with refluxing for from 1 to 5 hours. The proportionsof the reactant compounds preferably are such that the amount of thepalladium compound is about from 0.01 to 0.1 mol and the amount offormic acid or a formic acid amine salt is about from 3 to 15 mol, permol of the azetidin-2-one (I).

In the case where the raw compound is azetidin-2-one derivatives (Ia)represented by formula (I) in which R⁵ is a hydrogen atom, thede-esterification and decarboxylation reactions of these compoundsselectively yield α-alkyl isomers (IIα) as compounds (II). Although theconfiguration for the alkyl group at the 1-position in the carbapenembackbone of each of the final desired compounds is β-configuration, theα-alkyl isomers (IIα) obtained can be converted to β-alkyl isomers (IIβ)by isomerizing the α-alkyl isomers according to the known methoddescribed above.

On the other hand, in the case where the raw compound is azetidin-2-onederivatives (Ib) represented by formula (I) in which R⁵ is anamino-protective group, the desired compound (II) can be obtained byconducting the de-esterification and decarboxylation reactions asdescribed above and then eliminating the amino-protective group. Thisprocess preferred because β-alkyl isomer (IIβ) is preferentiallyobtained as compound (II) and is, hence, of high value in industrialutilization thereof. The elimination reaction for the amino-protectivegroup is conducted in different ways according to the kind of theprotective group. For example, in the case where the protective group isa tri-substituted silyl group, the elimination may be accomplished byreacting an acid such as diluted hydrochloric acid or tetrabutylammoniumfluoride. In the case where the protective group is benzyl, phenethyl,or benzhydryl group or the like which may have a substituent, theelimination may be carried out by reacting the de-esterified anddecarboxylated compound with sodium metal in liquid ammonia by means ofBirch's reduction.

According to the present invention, a 4-(1-carboxyalkyl)azetidin-2-onederivative useful as an intermediate for lβ-alkylcarbapenem-typeantibacterials can be produced efficiently.

The present invention will be explained below in more detail withreference to Examples, but the present invention is not construed asbeing limited thereto.

For the following measurements, the instruments specified below wereused.

Melting point:

Type MP-S3 (manufactured by Yanagimoto Shoji K. K., Japan) Mass spectrum(MS):

M-80B mass spectrometer (ionization potential: 20 eV) (manufactured byHitachi Ltd., Japan)

Infrared absorption spectrum (IR): Type IR-810 (manufactured by JASCOInc., Japan)

¹ H Nuclear magnetic resonance spectrum (¹ H-NMR): Type AM-400 (400 MHz)(manufactured by Bruker Inc.) Internal standard: tetramethylsilane

EXAMPLE 1 ##STR14## (In the above scheme, Ac has the meaning as definedhereinabove and TBDMS denotes a tert-butyldimethylsilyl group. The sameapplies hereinafter.)

In 50 ml of tetrahydrofuran was suspended 2.52 g (62.9 mmol) of 60%sodium hydride. While this suspension was kept being stirred at roomtemperature, a solution prepared by dissolving 11.88 g (60.0 mmol) ofdiallyl methylmalonate (VII-1) in 20 ml of tetrahydrofuran was addedthereto dropwise over a period of 20 minutes. After the resultingmixture was further stirred for 2.5 hours, a solution prepared bydissolving 14.35 g (50.0 mmol) of a 4-acetoxyazetidin-2-one derivative(IV-1) in 30 ml of tetrahydrofuran was added thereto dropwise over aperiod of 15 minutes, and a reaction was allowed to proceed at roomtemperature for 15 hours.

To the reaction mixture was added 30 ml of a saturated aqueous solutionof ammonium chloride. After stirring and liquid separation, thetetrahydrofuran layer obtained was washed with saturated aqueous commonsalt solution and dehydrated with anhydrous magnesium sulfate.Subsequently, the solvent was removed by distillation to obtain 23.5 gof crude crystals. This crude product was then recrystallized usinghexane, thereby obtaining 18.03 g (percent yield 85%) of anazetidin-2-one derivative (Ia-1) as white crystals.

Melting point: 82°-82.5° C. MS (m/e): 426 (M⁺ +1), 410, 368 IR (KBr)cm^(l) : 1765, 1735 ¹ H-NMR (CDCl₃) δ ppm: 0.07 (s, 6H), 0.88 (s, 9H),1.14 (d,J=6.3 Hz, 3H), 1.50 (s, 3H), 3.03 (m, 1H), 4.19 (d,J=2.1 Hz,1H), 4.21 (m, 1H), 4.64 (m, 4H), 5.27 (m, 2H), 5.34 (m, 2H), 5.88 (m,2H), 5.96 (broad s, 1H)

EXAMPLE 2 ##STR15##

Five ml of hexane was added to 1.12 g (28.0 mmol) of sodium hydride,subsequently the resulting mixture was stirred, and the hexane was thenremoved by decantation. This procedure was repeated several times towash the sodium hydride. Thereafter, 20 ml of tetrahydrofuran was addedto the sodium hydride. While this mixture was kept being stirred at roomtemperature, a solution prepared by dissolving 4.52 g (26.0 mmol) ofdiethyl methylmalonate (VII-2) in 20 ml of tetrahydrofuran was addedthereto dropwise over a period of 15 minutes. After the resultingmixture was further stirred for minutes, a solution prepared bydissolving 5.74 g (20.0 mmol) of a 4-acetoxyazetidin-2-one derivative(IV-I) in 20 ml of tetrahydrofuran was added thereto dropwise over aperiod of 10 minutes, and a reaction was allowed to proceed at roomtemperature for 1 hour.

To the reaction mixture was added 25 ml of a saturated aqueous solutionof ammonium chloride. After stirring and liquid separation, thetetrahydrofuran layer obtained was washed with saturated aqueous commonsalt solution and dehydrated with anhydrous magnesium sulfate.Subsequently, the solvent was removed by distillation to obtain crudecrystals. This crude product was then recrystallized using hexane,thereby obtaining 6.17 g (percent yield 77%) of an azetidin-2onederivative (Ia-2) as white crystals.

Melting point: 100.5°-101° C. MS (m/e): 402 (M⁺ +1 ), 386,344 IR (KBr)cm⁻¹ : 1770, 1735 ¹ H-NMR (CDCl₃) δ ppm: 0.07 (s, 6H), 0.88 (s, 9H),1.14 (d, J=6.3 Hz, 3H), 1.26, 1.28 (2 overlapping t, J=7.1 Hz, 6H), 1.46(s, 3H), 3.01 (m, 1H), 4.15 (d, J=2.2 Hz, 1H), 4.21 (m, 5H), 5.98 (broads, 1H)

EXAMPLE 3 ##STR16## (In the above scheme, Ph denotes a phenyl group. Thesame applies hereinafter.)

In 5 ml of tetrahydrofuran was suspended 0.43 g (10.8 mmol) of 60%sodium hydride. While this suspension was kept being stirred at roomtemperature, a solution prepared by dissolving 3.13 g (10.5 mmol) ofdibenzyl methylmalonate (VII-3) in 3 ml of tetrahydrofuran was addedthereto dropwise over a period of 20 minutes. After the resultingmixture was further stirred at room temperature for 30 minutes, asolution prepared by dissolving 2.87 g (10.0 mmol) of a4-acetoxyazetidin-2-one derivative (iV-1) in 5 ml of tetrahydrofuran wasadded thereto dropwise over a period of 15 minutes, and a reaction wasallowed to proceed at room temperature for 1.5 hours.

To the reaction mixture was added 15 ml of a saturated aqueous solutionof ammonium chloride. After stirring, extraction was conducted using 20ml of ethyl acetate. The ethyl acetate layer obtained was washed withwater, subsequently dehydrated with anhydrous magnesium sulfate, andthen concentrated, thereby to obtain an oily substance. This oilysubstance was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=4:1 by volume), thereby obtaining 4.28 g(percent yield 82%) of an azetidin-2one derivative (Ia-3) as whitecrystals.

Melting point: 93°-93.5° C. MS (m/e): 526 (M⁺ +1), 510, 468 IR (KBr)cm⁻¹ : 1770, 1735 ¹ H-NMR (CDCl₃) δ ppm: 0.06 (s, 6H), 0.87 (s, 9H),1.09 (d, J=6.4 Hz, 3H), 1.50 (s, 3H), 3.03 (m, 1H), 4.19 (m, 1H), 4.20(d, J=2.1 Hz, 1H), 5.11 (m, 4H), 5.89 (broad s, 1H), 7.23 (m, 4H), 7.32(m, 6H)

EXAMPLE 4 ##STR17##

In 15 ml of tetrahydrofuran was suspended 2.17 g (54.3 mmol) of 60%sodium hydride. While this suspension was kept being stirred at roomtemperature, a solution prepared by dissolving 10.9 g (54.0 mmol) oftert-butyl ethyl methylmalonate (VII-4) in 20 ml of tetrahydrofuran wasadded thereto dropwise over a period of 1 hour. After the resultingmixture was further stirred at room temperature for 30 minutes, asolution prepared by dissolving 14.1 g (49.1 mmol) of a4-acetoxyazetidin-2-one derivative (IV-1) in 30 ml of tetrahydrofuranwas added thereto dropwise over a period of 20 minutes, and a reactionwas allowed to proceed at room temperature overnight.

To the reaction mixture was added 50 ml of a saturated aqueous solutionof ammonium chloride. After stirring extraction was conducted using 50ml of ethyl acetate. The ethyl acetate layer obtained was washed twicewith 25 ml of saturated aqueous common salt solution, subsequentlydehydrated with anhydrous magnesium sulfate, and then filtered andconcentrated, thereby to obtain a crude product. This crude product waspurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=4:1 by volume), thereby obtaining 14.2 g (percentyield 67%) of an isomer mixture of azetidin-2-one derivatives (Ia-4) and(Ia-5) [isomer ratio (Ia-4):(Ia-5)=77:23 by mol] as white crystals.

Melting point: 73°-74° C. MS (m/e): 414, 372 IR (KBr) cm^(-l) : 1765,1735 ¹ H-NMR (CDCl₃) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H),1.15 (d, J=6.4Hz, 3H×23/100), 1.20 (d, J=6.3 Hz, 3H×77/100), 1.27 (d,J=7.1 Hz, 3H×77/100), 1.29 (d, J=7.1 Hz, 3H×23/100), 1.41 (s,3H×23/100), 1.42 (s, 3H×77/100), 1.45 (s, 9H×23/100), 1.47 (s,9H×77/100), 2.98 (m, 1H×23/100), 3.02 (m, 1H×77/100), 4.04 (d, J=2.1 Hz,1H×77/100), 4.09 (d, J=2.2 Hz, 1H× 23/100), 4.20 (m, 3H), 5.97 (broad s,1H)

EXAMPLE 5 ##STR18##

To 0.30 g (7.5 mmol) of 60% sodium hydride was added 3 ml of hexane.This mixture was stirred and the hexane was then removed by decantation.Thereafter, 3.5 ml of tetrahydrofuran was added to the sodium hydride.While the mixture was kept being stirred at room temperature, a solutionprepared by dissolving 2.96 g (7.5 mmol) of di-l-menthyl methylmalonate(VII-5) in 5 ml of tetrahydrofuran was added thereto dropwise over aperiod of 15 minutes. After the resulting mixture was further stirred atroom temperature for 30 minutes, a solution prepared by dissolving 2.01g (7.0 mmol) of a 4-acetoxyazetidin-2-one derivative (IV-1) in 5 ml oftetrahydrofuran was added thereto dropwise over a period of 10 minutes,and a reaction was allowed to proceed at room temperature for 1 hour.

To the reaction mixture was added 10 ml of a saturated aqueous solutionof ammonium chloride. After stirring and liquid separation, thetetrahydrofuran layer was washed with saturated aqueous common saltsolution and then dehydrated with anhydrous magnesium sulfate.Subsequently, the solvent was removed by distillation to obtain a crudeproduct. This crude product was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=8:1 by volume),thereby obtaining 2.94 g (percent yield 68%) of an azetidin-2-onederivative (Ia-6) which was colorless and had an oily consistency.

MS (m/e): 622 (M⁺ +1), 564 IR (neat) cm^(-l) : 1770, 1740, 1720 ¹ H-NMR(CDCl₃) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.72 (d, J=7.0 Hz, 3H), 0.77(d, J=7.0 Hz, 3H), 0.88 (s, 9H), 0.91 (d, J=6.7 Hz, 6H), 0.92 (d, J=6.5Hz, 0.95 (m, 6H), 1.22 (d, J=6.3 Hz, 3H), 1.42 (m 4H), 1.45 (s, 3H),1.70 (m, 4H), 1.86 (m, 2H), 2.03 (m, 2H), 3.10 (m, 1H), 4.06 (d, J=2.2Hzr 1H), 4.22 (m, 1H), 4.73 (m, 2H), 5.91 (s, 1H)

EXAMPLE 6 ##STR19##

In 50 ml of tetrahydrofuran was suspended 2.92 g (73.0 mmol) of 60%sodium hydride. While this suspension was kept being stirred at roomtemperature, a solution prepared by dissolving 33.07 g (73.0 mmol) ofdiallyl n-propylmalonate (VII-6) in 50 ml of tetrahydrofuran was addedthereto dropwise. After the resulting mixture was stirred for 2.5 hours,a solution prepared by dissolving 20.10 g (70.0 mmol) of a4-acetoxyazetidin-2-one derivative (IV-1) in 50 ml of tetrahydrofuranwas added thereto dropwise over a period of 30 minutes, and a reactionwas allowed to proceed at room temperature for 15 hours.

To the reaction mixture was added 60 ml of a saturated aqueous solutionof ammonium chloride. After stirring and liquid separation, thetetrahydrofuran layer obtained was washed with saturated aqueous commonsalt solution and dehydrated with anhydrous magnesium sulfate.Subsequently, the solvent was removed by distillation to obtain a crudeproduct This crude product was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=t10:1 byvolume), thereby obtaining 26.32 g (percent yield 83%) of anazetidin-2-one derivative (Ia-7) as white crystals.

Melting point: 47°-48° C. MS (m/e): 438, 396 IR (KBr) cm⁻¹ : 1770, 1730¹ H-NMR (CDCl₃) δ ppm: 0.07 (s, 6H), 0.88 (S, 9H), 0.94 (t, J=7.3Hz,3H), 1.17 (d, J=6.4 Hz, 3H), 1.25 (m, 1H), 1.47 (m, 1H), 1.80 (ddd,J=4.4, 12.5, 14.0 Hz, 1H), 1.97 (ddd, J=4.6, 12.7, 14.0 Hz, 1H) , 3.08(m, 1H), 4.25 (m, 2H), 4.65 (m, 4H), 5.30 (m, 4H), 5.88 (m, 3H)

EXAMPLE 7 ##STR20##

In 20 ml of N,N-dimethylformamide were dissolved 8.50 g (20.0 mmol) ofthe azetidin-2-one derivative (Ia-1) obtained in Example 1 and 6.04 g(40.0 mmol) of tert-butyldimethylsilyl chloride. To this solution, asolution prepared by dissolving 6.06 g (60.0 mmol) of triethylamine in 5ml of N,N-dimethylformamide was added dropwise at room temperature overa period of 15 minutes. After the resulting mixture was further stirredfor 4 hours, 0.12 g (1.0 mmol) of 4-N,N-dimethylaminopyridine was addedthereto, and a reaction was allowed to proceed at room temperature for 6days.

The reaction mixture was concentrated under a reduced pressure.Thereafter, 40 ml of water was added to the concentrate and extractionwas conducted using 200 ml of diethyl ether. The diethyl ether layerobtained was washed with 30 ml of saturated aqueous common salt solutionand then dehydrated with anhydrous magnesium sulfate. Subsequently, thesolvent was removed by distillation to obtain a crude product. Thiscrude product was purified by alumina column chromatography (developingsolvent; hexane:ethyl acetate=from 9:1 to 8:2 by volume), therebyobtaining 8.02 g (percent yield 74%) of an azetidin-2-one derivative (Ib-1) which was colorless and had an oily consistency.

MS (m/e): 540 (M⁺ +1), 524, 482 IR (neat) cm⁻¹ : 1760, 1740 ¹ H-NMR(CDCl ₃) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.11 (s, 3H), 0.29 (s, 3H),0.89 (s, 9H), 0.96 (s, 9H), 1.22 (d, J=6.2 Hz, 3H), 1.50 (s, 3H), 3.07(dd, J=2.6, 6.8 Hz, 1H), 4.09 (m, 1H), 4.35 (d, J=2.6 Hz, 1H), 4.64 (m,4H), 5.30 (m, 4H), 5.90 (m, 2H)

EXAMPLE 8 ##STR21##

In 13 ml of N,N-dimethylformamide were dissolved 1.70 g (4.0 mmol) ofthe azetidin-2-one derivative (Ia-1) obtained in Example 1 and 1.12 g(4.8 mmol) of methyldiphenylsilyl chloride. This solution was stirred inan ice bath. Thereto, a solution prepared by dissolving 0.48 g (4.8mmol) of triethylamine in 2 ml of N,N-dimethylformamide was addeddropwise over a period of 40 minutes. The resulting mixture was thenallowed to stand overnight in a refrigerator.

From the reaction mixture, the solvent was removed by distillation undera reduced pressure. Subsequently, 10 ml of water and 15 ml of ethylacetate were added to the residue and extraction was conducted. Theethyl acetate layer obtained was dehydrated with anhydrous magnesiumsulfate and the solvent was then removed by distillation, thereby toobtain an oily substance. This oily substance was purified by silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate =5:1 byvolume), thereby obtaining 1.69 g (percent yield 68%) of anazetidin-2-one derivative (Ib-2) which was colorless and had an oilyconsistency.

MS (m/e): 606,564,544 IR (neat) cm⁻¹ : 1755, 1735 ¹ H-NMR (CDCl₃) δ ppm:-0.02 (s, 3H), 0.06 (s, 3H), 0.82 (s, 3H), 0.88 (s, 9H), 1.14 (d, J=6.3Hz, 3H), 1.25 (s, 3H), 3.15 (m, 1H), 4.16 (m, 1H), 4.32 (m, 4H), 4.43(d, J=2.7 Hz, 1H), 5.18 (m, 4H), 5.71 (m, 2H), 7.47 (m, 10H)

EXAMPLE 9 ##STR22##

In 25 ml of N,N-dimethylformamide were dissolved 2.87 g (6.7 mmol) ofthe azetidin-2-one derivative (Ia-1) obtained in Example 1 and 1.58 g(10.5 mmol) of triethylsilyl chloride. This solution was stirred in anice bath. Thereto, a solution prepared by dissolving 1.06 g (10.5 mmol)of triethylamine in 5 ml of N,N-dimethylformamide was added dropwiseover a period of 20 minutes. The resulting mixture was then allowed tostand overnight in a refrigerator.

From the reaction mixture, the solvent was removed by distillation undera reduced pressure. Subsequently, 15 ml of a saturated aqueous solutionof sodium hydrogen carbonate and 25 ml of ethyl acetate were added tothe residue and extraction was conducted. The ethyl acetate layerobtained was dehydrated with anhydrous magnesium sulfate and the solventwas then removed by distillation, thereby to obtain an oily substance.This oily substance was purified by alumina column chromatography(developing solvent; hexane:ethyl acetate =10:1 by volume), therebyobtaining 2.20 g (percent yield 61%) of an azetidin-2-one derivative(Ib-3) which was colorless and had an oily consistency.

MS (m/e): 524,511, 482 IR (neat) cm⁻¹ : 1750 ¹ H-NMR (CDC1B) δ ppm: 0.06(s, 3H), 0.07 (s, 3H), 0.78 (m, 6H), 0.88 (s, 9H), 0.98 (t, J=7.8 Hz,9H), 1.26 (d, J=6.3 Hz, 3H), 1.49 (s, 3H), 3.05 (m, 1H), 4.12 (m, 1H),4.21 (d, J=2.6 Hz, 1H), 4.63 (m, 4H), 5.30 (m, 4H), 5.87 (m, 2H)

EXAMPLE 10 ##STR23##

In 5 ml of N,N-dimethylformamide was suspended 0.19 g (4.8 mmol) of 60%sodium hydride. This suspension was cooled to 0° C., and a solutionprepared by dissolving 1.93 g (4.5 mmol) of the azetidin-2-onederivative (Ia-1) obtained in Example 1 in 5 ml of N,N-dimethylformamidewas added thereto dropwise over a period of 10 minutes. After theresulting mixture was lo further stirred for 30 minutes, the temperatureof the mixture was returned to room temperature. Subsequently, 0.58 g(4.6 mmol) of benzyl chloride was added thereto dropwise and a reactionwas allowed to proceed for 4 hours.

To the reaction mixture was added 5 ml of a saturated aqueous solutionof ammonium chloride. Extraction was then conducted with 50 ml ofdiethyl ether. The diethyl ether layer obtained was dehydrated withanhydrous magnesium sulfate and the solvent was then removed bydistillation, thereby to obtain a crude product. This crude product waspurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=4:1 by volume), thereby obtaining 1.57 g (percentyield 68) of an azetidin-2-one derivative (Ib-4) which was colorless andhad an oily consistency.

MS (m/e): 516 (M⁺ +1), 500, 458 IR (neat) cm⁻¹ : 1760, 1740 ¹ H-NMR(CDCl₃) δ ppm: -0.01 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H), 1.13 (d, J=6.3Hz, 3H), 1.31 (s, 3H), 2.99 (m, 1H), 4.18 (m, 1H), 4.23 (d, J=15.4 Hz,1H), 4.31 (d, J=2.1 Hz, 1H), 4.57 (m, 5H), 5.28 (m, 4H), 5.83 (m, 2H),7.31 (m, 5H)

EXAMPLE 11 ##STR24##

Using 2.13 g (5.0 mmol) of the azetidin-2-one derivative (Ia-1) obtainedin Example 1, 0.22 g (5.5 mmol) of 60% sodium hydride, and 1.25 g(5.5mmol) of p-tert-butylbenzyl bromide, N-benzylation was conducted inthe same manner as in Example 10. Thus, 2.27 g (percent yield 79%) of anazetidin-2-one derivative (Ib-5) was obtained which was colorless andhad an oily consistency.

MS (m/e): 556, 514 IR (neat) cm⁻¹ : 1765, 1740 ¹ H-NMR (CDCl₃) δ ppm:-0.06 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.13 (d, J=6 . 3 Hz, 3H),1.29 (s, 9H), 1.33 (s, 3H), 2.98 (dd, J=2.1, 4.5 Hz, 1H), 4.13 (d,J=15.3 Hz, 1H), 4.14 (m, 1H), 4.35 (d, J=2.1 Hz, 1H), 4.52 (m, 5H), 5.27(m, 4H), 5.80 (m, 4H), 7.29 (m, 4H)

EXAMPLE 12 ##STR25##

Using 2.13 g (5.0 mmol) of the azetidin-2-one derivative (Ia-1) obtainedin Example 1, 0.24 g (6.0 nmol) of sodium hydride, and 0.94 g (6.0 mmol)of p-methoxybenzyl chloride, N-benzylation was conducted in the samemanner as in Example 10. Thus, 2.07 g (percent yield 76%) of anazetidin-2-one derivative (Ib-6) was obtained which was colorless andhad an oily consistency.

MS(m/e): 488 IR (neat) cm⁻¹ : 1760, 1735 ¹ H-NMR (CDCl₃) δ ppm: 0.01 (s,3H), 0.05 (s, 3H), 0.85 (s, 9H), 1.13 (d, J=6 .3 Hz, 3H ) , 1.30 (s,3H), 2.98 (dd, J=2.1, 4.3 Hz, 1H), 3.79 (s, 3H), 4.16 (m, 1H) , 4.18 (d,J=15.2 Hz, 1H), 4.37 (d, J=2.1 Hz, 1H), 4.43 (d, J=15.2 Hz, 1H), 4.59(m, 4H) , 5.28 (m, 4H), 5.82 (m, 2H), 6.83 (dd, J=2.1, 6.3 HZ, 2H), 7.27(dd, J=2.1, 6.3 Hz, 2H)

EXAMPLE 13 ##STR26##

Using 4.01 g (10.0 mmol) of the azetidin-2-one derivative (Ia-2)obtained in Example 2, 0.40 g (11.0 mmol) of sodium hydride, and 1.39 g(11.0 mmol) of benzyl chloride, N-benzylation was conducted in the samemanner as in Example 10. Thus, 4.30 g (percent yield 88%) of anazetidin-2-one derivative (Ib-7) was obtained which was colorless andhad an oily consistency.

MS(m/e): 476,434 IR (neat) cm⁻¹ : 1760, 1730 ¹ H-NMR (CDC13) δ ppm: 0.00(s, 3H), 0.06 (s, 3H), 0.87 (s, 9H), 1.16 (d, J=6.3 Hz, 3H), 1.20, 1.22(2 overlapping t, J=7.3 Hz, 6H), 1.30 (s, 3H), 2.99 (dd, J=2.1, 4.5 Hz,1H), 4.17 (m, 6H), 4.36 (d, J=2.1 Hz, 1H), 4.55 (d, J=15.3 Hz, 1H), 7.31(m, 5H)

EXAMPLE 14 ##STR27##

To 0.40 g (10.0 mmol) of 60% sodium hydride was added 5 ml of hexane.This mixture was stirred and the hexane was then removed by decantation.To the sodium hydride was added 25 ml of N,N-dimethylformamide.Subsequently, 4.65 g (8.9 mmol) of the azetidin-2-one derivative (Ia-3)obtained in Example 3 was added thereto at room temperature. After theresulting mixture was further stirred at room temperature for 30minutes, a solution prepared by dissolving 1.12 g (8.9 mmol) of benzylchloride in 4 ml of N,N-dimethylformamide was added thereto dropwiseover a period of 5 minutes, and the mixture was kept being stirredovernight at room temperature.

From the reaction mixture, the solvent was removed by distillation undera reduced pressure. Subsequently, 15 ml of a saturated aqueous solutionof sodium hydrogen carbonate and 35 ml of ethyl acetate were added tothe residue and extraction was conducted. The ethyl acetate layerobtained was dehydrated with anhydrous magnesium sulfate and the solventwas then removed by distillation, thereby to obtain an oily substance.This oily substance was purified by silica gel column chromatography(developing solvent; hexane:ethyl acetane=2:1 by volume), therebyobtaining 3.50 g (percent yield 64%) of an azetidin-2-one derivative(Ib-8) which was colorless and had an oily consistency.

MS (m/e): 600, 558 IR (neat) cm⁻¹ : 1760, 1730 ¹ H-NMR (CDCl₃) δ ppm:-0.03 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.10 (d, J=6.3 Hz, 3H), 1.30(s, 3H), 3.00 (dd, J=2.1, 4.4 Hz, 1H), 4.12 (d, J=15.4 Hz, 1H), 4.15 (m,1H), 4.37 (d, J=15.4 Hz, 1H), 4.40 (d, J=2.1 Hz, 1H), 4.94 (d, J=12.2Hz, 1H), 5.06 (m, 3H), 7.26 (m, 15H)

EXAMPLE 15 ##STR28##

In an argon stream, 4.8 mg (0.02 mmol) of palladium acetate wassuspended in 2 ml of 1,4-dioxane, and a solution prepared by dissolving52.0 mg (0.2 mmol) of triphenylphosphine in 2 ml of 1,4-dioxane wasadded dropwise to the suspension. Subsequently, the resulting mixturewas heated with refluxing and, further, a solution prepared bydissolving 0.85 g (2.0 mmol) of the azetidin-2-one derivative (Ia-1)obtained in Example 1, 0.37 g (7.9 mmol) of formic acid, and 0.81 g (8.0mmol) of triethylamine in 6 ml of 1,4-dioxane was added theretodropwise. A reaction was then allowed to proceed for 3 hours.

To the reaction mixture were added 10 ml of a 5% aqueous solution ofsodium hydroxide and 10 ml of ethyl. acetate. After liquid separation,the aqueous layer was acidified with in hydrochloric acid and extractionwas then conducted with 20 ml of ethyl acetate. The ethyl acetate layerobtained was dehydrated with anhydrous magnesium sulfate and the solventwas then removed by distillation, thereby obtaining 0.47 g (percentyield 78%) of the desired compound, a 4-(1-carboxyethyl)-azetidin-2-onederivative (II-1), as white crystals.

In the compound (II-1) thus obtained, the proportions of compound(IIα-1) in which the methyl group at the wavy line in the formulashowing the compound (II-1) was of the α-configuration and compound(IIβ-1) in which that methyl group was of the β-configuration were suchthat α:β=85:15 (by mol). This structure determination was made byseparating these isomers by means of high-performance liquidchromatography (HPLC) (column; Inertsil ODS, manufactured by GL SciencesInc., Japan, developing solvent; acetonitrile:water:acetic acid=700:300:3 by volume).

Isomer (IIα-1)

Melting point: 168°-170° C. MS (m/e): 286, 244 IR (KBr ) cm^(-l) : 1720¹ H-NMR (CDCl ₃) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H) 1.25 (2overlapping d, J=6.2, 7.3 Hz, 6H), 2.56 (qd, J=7.3, 9.8 Hz, 1H), 2.80(dd, J=2.0, 5.3 Hz, 1H), 3.70 (dd, J=2.0, 9.8 Hz, 1H), 4.19 (m, 1H),6.67(broad s, 1H)

Isomer (IIβ-1)

Melting point: 143.5°--144.5° C. MS (m/e): 286, 244 IR (KBr ) cm^(-l) :1720 ¹ H-NMR (CDCl ₃ ) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H),1.20 (d, J=6.3 Hz, 3H), 1.27 (d, J=7.0 Hz, 3H), 2.75 (qd, J=5.0, 7.0 Hz,1H), 3.03 (dd, J=2.2, 4.3 Hz, 1H), 3.94 (dd, J=2.2, 5.0 Hz, 1H), 4.20(qd, J=4.5, 6.3 Hz, 1H),6.25 (broad s, 1H)

EXAMPLE 16 ##STR29##

In a nitrogen atmosphere, a solution prepared by dissolving 746.0 mg(16.22 mmol) of formic acid and 1,647.7 mg (16.31mmol) of triethylaminein 10 ml of 1,4-dioxane was added to a solution prepared by dissolving9.0 mg (0.04 mmol) palladium acetate and 53.0 mg (0.20mmol) oftriphenylphosphine in 8 ml of 1,4-dioxane, and this mixture was heatedwith refluxing. Thereto was added dropwise, over a period of 40 minutes,a solution prepared by dissolving 1,815.4 mg (4.01 mmol) of theazetidin-2-one derivative (Ia-7) obtained in Example 6 in 5 ml of1,4-dioxane. The resulting mixture was kept being heated with refluxingfor further 5 hours.

The reaction mixture was cooled to room temperature, and extraction wasconducted with 15 ml of diethyl ether and 20 ml of a 5% aqueous solutionof sodium hydroxide. Subsequently, 2N hydrochloric acid was added to thealkaline layer to adjust it to pH 2, and extraction was conducted withtwo 35 ml portions of ethyl acetate. The ethyl acetate layer obtainedwas washed with saturated aqueous common salt solution, subsequentlydehydrated with anhydrous magnesium sulfate, and then filtered andconcentrated, thereby obtaining 985.8 mg (percent yield 75%) of thedesired compound, a 4-(1-carboxybutyl)azetidin-2-one derivative (II-2),as white crystals.

In the compound (II-2) thus obtained, the proportions of compound(IIα-2) in which the n-propyl group at the wavy line in the formulashowing the compound (II-2) was of the α-configuration and compound(IIβ-2) in which that n-propyl group was of the β-configuration weresuch that α:β=73:27 (by mol). This structure determination was made byseparating these isomers by means of HPLC (conditions concerning thecolumn ant developing solvent were the same as those in Example 15).

αIsomer (IIα-2) Melting point: 173°-174° C. MS (m/e): 314, 272 IR (KBr)cm⁻¹ : 1720 ¹ H-NMR (CD₃ OD) δ ppm: 0.08 (s, 3H), 0.10 (s, 3H), 0.90 (s,9H) , 0.94 (t, J=7.2 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H), 1.40 (m, 2H), 1.60(m, 2H), 2.47 (m, 1H), 2.88 (dd, J=2.0, 4.3 Hz, 1H), 3.78 (dd, J=2.0,8.7 Hz, 1H), 4.20 (qd, J=4.3, 6.3 Hz, 1H)

βIsomer (IIβ-2 )

Melting point: 164.5°-166° C. MS (m/e): 314, 272 IR (KBr) cm⁻¹ : 1720 ¹H-NMR (CD₃ OD ) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H) , 0.95(t, J=7.2 Hz, 3H), 1.16 (d, J=6.4 Hz, 3H), 1.45 (m, 3H), 1.64 (m, 1H),2.48 (m, 1H), 3.01 (dd, J=2.0, 2.7 Hz, 1H), 3.77 (dd, J=2.0, 8.4 Hz,1H), 4.22 (qd, J=2.7, 6.4 Hz, 1H)

EXAMPLE 17 ##STR30##

In a nitrogen atmosphere, 0.56 g (12.0 mmol)of formic acid was added toa solution prepared by dissolving 4.5 mg (0.02 mmol) of palladiumacetate and 10.5 mg (0.04 mmol) of triphenylphosphine in 2.5 ml oftoluene, and this mixture was stirred with heating at 70° C. To thisreaction mixture was added dropwise, over a period of 15 minutes, asolution prepared by dissolving 0.54 g (1.0 mmol) of the azetidin-2-onederivative (Ib-1) obtained in Example 7 in 2 ml of toluene. The mixturewas then kept being further stirred at 70° C. for 3.5 hours.

The reaction mixture was cooled to room temperature and ml of diethylether and 5 ml of 2N hydrochloric acid were added thereto. After theresulting mixture was stirred for 20 minutes, liquid separation wasconducted. The diethyl ether layer was extracted with three 10 mlportions of a 5% aqueous solution of sodiumhydroxide. Thereafter, 2Nhydrochloric acid was added to the aqueous layer to adjust it to pH 2and extraction was conducted with two 20 ml portions of diethyl ether.The diethyl ether layer obtained was washed with saturated aqueouscommon salt solution, subsequently dehydrated with anhydrous magnesiumsulfate, and then filtered and concentrated, thereby obtaining 0.23 g(percent yield 76%) of the desired compound (II-1).

In the compound (II-1) thus obtained, the proportions of isomers weresuch that (IIα-1):(IIβ-1)=6:94 (by mol).

EXAMPLE 18 ##STR31##

In a nitrogen atmosphere, a solution prepared by dissolving 2.02 g (44.0mmol) of formic acid and 5.55 g (55.0 mmol) of triethylamine in 15 ml oftetrahydrofuran was added to a solution prepared by dissolving 24.8 mg(1.1 mmol) of palladium acetate and 57.6 mg (2.2 mmol) oftriphenylphosphine in 15 ml of tetrahydrofuran, and this mixture washeated with refluxing. To this reaction mixture was added dropwise, overa period of 30 minutes, a solution prepared by dissolving 5.68 g (11.0mmol) of the azetidin-2-one derivative (Ib-4) obtained in Example 10 in20 ml of tetrahydrofuran. The resulting mixture was kept being stirredfor further 1.5 hours.

The reaction mixture was cooled to room temperature and 80 ml of diethylether was added thereto. After liquid separation, the mixture was washedwith 30 ml of saturated aqueous common salt solution and dehydrated withanhydrous magnesium sulfate. The solvent was then removed bydistillation under a reduced pressure thereby to obtain 4.41 g of acrude product.

Subsequently, 1.29 g (56.0 mmol) of sodium metal was added to 100 ml ofliquid ammonia cooled to -60° C. Immediately after the sodium haddissolved and the liquid had turned dark blue, a solution prepared bydissolving 4.41 g of the crude product obtained above in 20 ml ofdiethyl ether was added thereto dropwise over a period of 30 minutes.Cooling of the reactor was stopped, and the temperature of the reactionmixture was returned to room temperature over a period of one nightwhile the reaction mixture was kept being stirred. To the resultingreaction mixture were added 50 ml of diethyl ether and 50 ml of water.This mixture was stirred and liquid separation was then conducted. Tothe aqueous layer obtained, an extract was added which had been obtainedby extracting the diethyl ether layer with 20 ml of a 5% aqueoussolution sodium hydroxide. Subsequently, the resulting mixture wasadjusted to pH 2 with diluted hydrochloric acid. This mixture wasextracted with 100 ml of diethyl ether, and the extract was washed with30 ml of saturated aqueous common salt solution, subsequently dehydratedwith anhydrous magnesium sulfate, and then filtered and concentrated,thereby obtaining 2.60 g (percent yield 77%) of the desired compound(II-1).

In the compound (II-1) thus obtained, the proportions of isomers weresuch that (IIα1):(IIβ1)=31:69 (by mol).

EXAMPLE 19 ##STR32##

Using 1.09 g (2.0 mmol) of the azetidin-2-one derivative (Ib-6) obtainedin Example 12, 9.0 mg (0.04 mmol) of palladium acetate, 21.0 mg (0.08mmol) of triphenyiphosphine, 0.37 g (8.0 mmol) of formic acid, and 0.91g (9.0 mmol) of triethylamine, de-esterification and decarboxylationreactions were conducted in the same manner as in Example 18.Subsequently, debenzylation reaction was performed using 30 ml of liquidammonia and 0.24 g (10.0 mmol) of sodium metal. Thus, 0.48 g (percentyield 80%) of the desired compound was obtained.

In the compound (II-1) thus obtained, the proportions of isomers weresuch that (IIα-1):(IIβ-1)=39:61 (by mol).

EXAMPLE 20 ##STR33##

In 30 ml of methanol were suspended 1.58 g (3.0 mmol) of theazetidin-2-one derivative (Ia-3) obtained in Example 3, 0.72 g (7.1mmol) of triethylamine, and 0.3 g of 5% palladium carbon. Hydrogenationwas then conducted at ordinary pressure.

The palladium carbon was removed from the resulting reaction mixture byfiltration. Thereafter, the methanol was removed by distillation under areduced pressure, and 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate and 10 ml of ethyl acetate were added to the residue.This mixture was stirred and liquid separation was conducted. Theaqueous layer was acidified with iN hydrochloric acid and the whitesolid thus formed was filtered off, washed with water, and then driedunder a reduced pressure, thereby obtaining 0.54 g (percent yield 52%)of a dicarboxylic acid compound (VIIIa).

Melting point: 110°-111° C. MS (m/e): 244, 200 IR (KBr) cm⁻¹ : 1755,1720 ¹ H-NMR (CD30D) δ ppm: 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),1.13 (d, J=6.4 Hz, 3H), 1.33 (s, 3H), 3.01 (dd, J=2.1, 2.7 Hz, 1H), 4.19(d, J=2.1 Hz, 1H) 4.20 (m, 1H)

EXAMPLE 21 ##STR34##

In a mixture of 15 ml of ethanol and 5 ml water was dissolved 1.08 g(2.7 mmol) of the azetidin-2-one derivative (Ia-2) obtained in Example2. Thereto was added a solution prepared by dissolving 0.99 g (17.6mmol) of potassium hydroxide in 3 ml of water. This mixture was keptbeing stirred for 5 hours with heating at 50° C.

The reaction mixture was cooled to room temperature and then poured into30 ml of water. The resulting mixture was acidified with 2N hydrochloricacid and the white solid thus formed was filtered off, washed withwater, and then dried under a reduced pressure, thereby obtaining 0.63 g(percent yield 68%) of a dicarboxylic acid compound (VIIIa).

EXAMPLE 22 ##STR35##

In 2 ml of ethanol was dissolved 0.40 g (0.93 mmol) of the isomermixture consisting of azetidin-2-one derivatives (Ia-4) and (Ia-5)obtained in Example 4. Thereto was added a solution prepared bydissolving 0.34 g (6.1 mmol) of potassium hydroxide in 3 ml of water.This mixture was kept being stirred at 50° C. for 2 days.

The reaction mixture was concentrated under a reduced pressure and iNhydrochloric acid was then added thereto to adjust it to pH 2.Thereafter, the resulting mixture was further concentrated under areduced pressure. To the solid thus obtained, 10 ml of diethyl ether wasadded. This mixture was stirred sufficiently and then filtered andconcentrated, thereby obtaining 0.21 g (percent yield 66%) of adicarboxylic acid compound (VIIIa).

EXAMPLE 23 ##STR36##

In a mixture of 10 ml of ethanol and 3 ml of water was dissolved 0.62 g(1.0 mmol) of the azetidin-2-one derivative (Ia-6) obtained in Example5. Thereto was added a solution prepared by dissolving 0.38 g (6.8mmol)of potassium hydroxide in 3 ml of water. This mixture was kept beingstirred at 50° C. for 25 hours.

The reaction mixture was cooled to room temperature and then poured into30 ml of water. Extraction was conducted with two 10 ml portions ofdiethyl ether. The aqueous layer obtained was acidified with 2Nhydrochloric acid and extraction was conducted with two 15 ml portionsof ethyl acetate. Subsequently, the extract was dehydrated withanhydrous magnesium sulfate and then filtered and dried under a reducedpressure, thereby obtaining 0.18 g (percent yield 52%) of a dicarboxylicacid compound (VIIIa).

EXAMPLE 24 ##STR37##

To 2.40 g (4.9 mmol) of the azetidin-2-one derivative (Ib-7) obtained inExample 13 were added 5 ml of ethanol and 10 ml of water. Thereto wasadded, with stirring, a solution prepared by dissolving 1.10 g (19.6mmol) of potassium hydroxide in 5 ml of water. This mixture was stirredovernight at room temperature.

The resulting reaction mixture was poured into 50 ml of water and 1Nhydrochloric acid was added thereto to adjust it to pH 7. Extraction wasthen conducted using 50 ml of diethyl ether. Thereafter, 1N hydrochloricacid was added to the extract until it became pH 1, and 50 ml of diethylether was then added thereto to conduct extraction. The diethyl etherlayer obtained was washed with 15 ml of saturated aqueous common saltsolution, subsequently dehydrated with anhydrous magnesium sulfate, andthen filtered and concentrated, thereby obtaining 1.50 g (percent yield69%) of a dicarboxylic acid compound (VIIIb).

Melting point: 128°-129° C. MS (m/e): 334,290 IR (KBr) cm⁻¹ : 1750, 1730¹ H-NMR (CD₃ OD) δ ppm: 0.01 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 1.16(d, J=6.4 Hz, 3H), 1.21 (s, 3H), 3.04 (m, 1H), 4.21 (m, 1H), 4.30 (d,J=15.2 Hz, 1H), 4.45 (d, J=2.1 Hz, 1H), 4.46 (d, J=15.2 Hz, 1H), 7.30(m, 5H)

EXAMPLE 25 ##STR38##

In 15 ml of diethylene glycol dimethyl ether was dissolved 1.38 g (4.0mmol) of the dicarboxylic acid compound (VIIIa) obtained in Examples 20to 23. This solution was heated at 120° C. for 3 hours.

The reaction mixture was cooled to room temperature and extraction wasthen conducted using 20 ml of diethyl ether and 15 ml of a 5% aqueoussolution of sodium hydroxide. Thereafter, the aqueous layer was washedwith 10 ml of diethyl ether and then adjusted to pH 2 with 2Nhydrochloric acid, and extraction was conducted using 30 ml of diethylether. The diethyl ether layer obtained was washed with 10 ml ofsaturated aqueous common salt solution, subsequently dehydrated withanhydrous magnesium sulfate, and then filtered and concentrated, therebyobtaining 0.97 g (percent yield 80%) of the desired compound (II-1).

In the compound (II-1) thus obtained, the proportions of isomers weresuch that (IIα1):(IIβ1)=90:10 (by mol).

EXAMPLE 26 ##STR39##

In the same manner as in Example 23, 0.87 g (2.0 mmol) of thedicarboxylic acid compound (VIIIb) obtained in Example 24 was heated toconduct decarboxylation reaction. Thereafter, debenzylation reaction wasperformed using liquid ammonia and sodium metal in the same manner as inExample 18, thereby obtaining 0.42 g (percent yield 70%) of the desiredcompound (II-1).

In the compound (II-1) thus obtained, the proportions of isomers weresuch that (IIα1):(IIβ1)=28:72 by mol).

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A 4-(1,1-dialkyloxycarbonylalkyl)azetidin-2-onederivative represented by formula (I): ##STR40## wherein R¹ and R² areidentical or different and each represents an alkyl group, an alkenylgroup, or an aralkyl group, R³ represents an alkyl group having from 1to 4 carbon atoms, R⁴ represents a hydrogen atom or ahydroxyl-protective group, and R⁵ represents a hydrogen atom or anamino-protective group.
 2. The4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative as claimed inclaim 1, wherein R⁵ is an amino-protective group selected from the groupconsisting of a tri-substituted silyl group which is selected from thegroup consisting of a trimethylsilyl group, a triethylsilyl group, atert-butyldimethylsilyl group and a methyldiphenylsilyl group, anaralkyl group which may have a substituent on the aromatic ring or ringswhich is selected from the group consisting of a benzyl group, ap-methoxybenzyl group, a p-tert-butylbenzyl group, a 3,4-dimethylbenzylgroup, a phenethyl group and a benzhydryl group; and an alkoxyalkylgroup.
 3. The 4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative asclaimed in claim 1, wherein R⁵ is a tri-substituted silyl group which isselected from the group consisting of a trimethylsilyl group, atriethylsilyl group, a tert-butyldimethylsilyl group, and amethyldiphenylsiyl group.
 4. The4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative as claimed inclaim 1, wherein R¹ and R² are identical and each is a 2-alkenyl group.5. The 4-(1,1-dialkoxycarbonylalkyl)azetidin-2-one derivative as claimedin claim 1, wherein R⁴ is a hydroxyl-protective group selected from thegroup consisting of a tri-substituted silyl group which is selected fromthe group consisting of a trimethylsilyl group and atert-butyldimethylsilyl group, an acetyl group, and an aralkyl group. 6.The 4- ( 1,1-dialkoxycarbonylalkyl )azetidin-2-one derivative as claimedin claim 1, wherein R³ is a methyl group.